7LT0

Hsp90a N-terminal inhibitor

Summary for 7LT0

• Entry DOI: 10.2210/pdb7lt0/pdb
• Descriptor: Heat shock protein HSP 90-alpha, (1,3-dihydro-2H-isoindol-2-yl){3-[(3,4-dimethylphenyl)sulfanyl]-4-hydroxyphenyl}methanone (3 entities in total)
• Functional Keywords: inhibitor, hsp90, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33875.72

Authors

Balch, M.,Peng, S.,Deng, J.,Matts, R. (deposition date: 2021-02-18, release date: 2021-03-03, Last modification date: 2023-10-18)

Primary citation

Mishra, S.J.,Khandelwal, A.,Banerjee, M.,Balch, M.,Peng, S.,Davis, R.E.,Merfeld, T.,Munthali, V.,Deng, J.,Matts, R.L.,Blagg, B.S.J.
Selective Inhibition of the Hsp90 alpha Isoform.
Angew.Chem.Int.Ed.Engl., 60:10547-10551, 2021

PubMed Abstract: The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N-terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan-inhibition of all four Hsp90 isoforms. Therefore, the development of isoform-selective Hsp90 inhibitors is sought to delineate the pathological role played by each isoform. Herein, we describe a structure-based approach that was used to design the first Hsp90α-selective inhibitors, which exhibit >50-fold selectivity versus other Hsp90 isoforms.

PubMed: 33621416
DOI: 10.1002/anie.202015422

Experimental method

X-RAY DIFFRACTION (1.697 Å)